ArticleAmerican journal of human genetics2018
Identification of Misclassified ClinVar Variants via Disease Population Prevalence.
Article in American journal of human genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 74 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
74 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Predicting Functional Effects of Synonymous Variants: A Systematic Review and Perspectives.Frontiers in genetics · 2019Pooled it
- The Time Lag Associated With the Reclassification of Germline BRCA Variants' Pathogenicity Is Critical for Cancer Patients.Cancer science · 2025Article
- Machine learning-based penetrance of genetic variants.Science (New York, N.Y.) · 2025Article
- Using large-scale population-based data to improve disease risk assessment of clinical variants.Nature genetics · 2025Review
- Clinical Features of Brugada Syndrome Patients With SCN5A Variants.Journal of cardiovascular electrophysiology · 2025Article
- Genetic disease risks of under-represented founder populations in New York City.PLoS genetics · 2025Article
- Development of multiplexed orthogonal base editor (MOBE) systems.Nature biotechnology · 2025Article
- Uncovering ASO-Targetable Deep IntronicDNA and cell biology · 2025Article
- Benchmarking of variant pathogenicity prediction methods using a population genetics approach.Bioinformatics advances · 2025Article
- Ensemble and consensus approaches to prediction of recessive inheritance for missense variants in human disease.Cell reports methods · 2024Article
- Guidance for estimating penetrance of monogenic disease-causing variants in population cohorts.Nature genetics · 2024Review
- Estimating cancer risk in carriers of Lynch syndrome variants in UK Biobank.Journal of medical genetics · 2024Article
- Two Japanese families with familial pancreatic cancer with suspected pathogenic variants of CDKN2A: a case report.Hereditary cancer in clinical practice · 2024Article
- Variant Effect Prediction in the Age of Machine Learning.Cold Spring Harbor perspectives in biology · 2024Review
- Article
- Underrepresentation of Diverse Ancestries Drives Uncertainty in Genetic Variants Found in Cardiomyopathy-Associated Genes.JACC. Advances · 2024Article
- Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity.Genome medicine · 2023Article
- Clinical risk management of breast, ovarian, pancreatic, and prostatic cancers for BRCA1/2 variant carriers in Japan.Journal of human genetics · 2023Review
- In vivo versus in silico assessment of potentially pathogenic missense variants in human reproductive genes.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- ClinVar and HGMD genomic variant classification accuracy has improved over time, as measured by implied disease burden.Genome medicine · 2023Article
14 more citing papers are in PubMed but not listed here.
Corrections and comments
- Commented on by
- Commented on by
- Commented on by
- Commented on by
Authors and funding
7 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
There is a significant interest in the standardized classification of human genetic variants. We used whole-genome sequence data from 10,495 unrelated individuals to contrast population frequency of pathogenic variants to the expected population prevalence of the disease. Analyses included the ACMG-recommended 59 gene-condition sets for incidental findings and 463 genes associated with 265 OrphaNet conditions. A total of 25,505 variants were used to identify patterns of inflation (i.e., excess genetic risk and misclassification). Inflation increases as the level of evidence supporting the pathogenic nature of the variant decreases. We observed up to 11.5% of genetic disorders with inflation in pathogenic variant sets and up to 92.3% for the variant set with conflicting interpretations. This improved to 7.7% and 57.7%, respectively, after filtering for disease-specific allele frequency. The patterns of inflation were replicated using public data from more than 138,000 genomes. The burden of rare variants was a main contributing factor of the observed inflation, indicating collective misclassified rare variants. We also analyzed the dynamics of re-classification of variant pathogenicity in ClinVar over time, which indicates progressive improvement in variant classification. The study shows that databases include a significant proportion of wrongly ascertained variants; however, it underscores the critical role of ClinVar to contrast claims and foster validation across submitters.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.